The primary objective is to test the hypothesis is that in patients with T2DM, treatment strategies that are designed to reach both a targeted level of glycemic control and lower plasma NEFA and TG levels will be associated with a greater decline in the dependence of the myocardium on fatty acid metabolism and a greater improvement myocardial diastolic function than treatment strategies designed solely to reach a target level of glycemic control. The specific aims are: 1A. To assess the impact of lowering plasma NEFA in patients with T2DM, we will determine the effect of adding the PPARgamma agonist rosiglitazone (ROSI) to a regimen of metformin +/- other non-thiazolidinedioneoral agents (MET) on whole-body substrate metabolism and on myocardial substrate metabolism and function. 1B. To assess the impact of lowering plasma TG in patients with T2DM, we will determine the effect of adding an extended-release niacin agent, niaspan (NI) to MET on whole-body substrate metabolism and on myocardial substrate metabolism and function. We will perform a series of experiments that utilize PET quantification of myocardial substrate metabolism, echocardiographic measurements of left ventricular systolic and diastolic function and stable isotopic measurements of whole-body fatty acid and glucose kinetics in T2DM patients. The measurements will be obtained in three groups of patients, those on MET alone those on MET and ROSI and those and NI. A secondary objective of this project is to perform "proof of concept" studies in humans for the best candidate from each class of new PET radiotracers developed in Project 1 and characterized in Project 6. The four classes to be studied are radiotracers designed to image PPARalpha, PPARgamma, iNOS activity and apoptosis/necrosis. When combined with the results from Project 6, alterations in whole-body and myocardial substrate metabolism in response to specific interventions observed in humans with T2DM will be linked to changes in gene expression in the rodent models undergoing the same interventions. These data may potentially provide support for a paradigm shift in the treatment of T2DM through the incorporation of therapies designed to decrease NEFA delivery to the heart.